Antibacterial therapeutical preparations



preparations.

Patented July 1, 1952 ANTIBACTERIAL THERAPEUTICAL PREPARATIONS Hermann Vollmer, New York, N. Y., assignor t Sharp & Dohme Incorporated, West Point, Pa., a corporation of Maryland No Drawing. Application April 22, 1952,

Serial No. 283,755

12 Claims. (01. 167-51.5)

The present application is a continuation-inpart of my copending U. S. patent application Serial No. 198,503, filed November 30, 1950, for Antibacterial Therapeutical Preparations, which in turn is a continuation-impart of my copending U. S. patent application Serial No. 2,853, filed January 1'7, 1948, for Antibacterial Therapeutical Preparations, now abandoned.

My present invention relates to antibacterial therapeutic preparations.

It is an object of my present invention to provide therapeutic preparations having entirely new ways of antibacterial action.

It is a further object of my present invention to provide therapeutic preparations having an intensified antibacterial action.

In accordance with my concept of biostrategy," which will be more fully explained later,

' i. e. the application of strategic principles in warfare against microorganisms, I propose to use therapeutic preparations comprising a combination of sulfonamides and penicillin. Due to competitive absorption by the gastro-intestinal tract, the individual agents of this combination enter the bloodstream in succession and reach their highest blood concentration at different times after oral administration of said therapeutic An example will explain the bio-strategic effect of my preparations:

A particularly preferred preparation according to my present invention consists of a combination of sulfadiazine, penicillin and sulfame'razine' as co-active ingredients.

' If, after oral administration of this preparation, the sulfadiazine reaches its maximum blood concentration, the weaker strains of bacteria are killed, while the stronger survive by adapting themselves to sulfadiazine.

This adaptation consists of an altered cell metabolism within the microorganism specifically directed against a specific chemotherapeutic agent and essentially different with different such agents. Such adaptation enables the mi-' croorganisms to survive in a given sulfadiazine concentration, but weakens them against any following, unexpected attack from another agent, which is entirely different in nature, and in antibacterial action.

At this moment, the penicillin reaches its maximum blood cencentration and hits the surviv- -ing bacilli more destructively than if they were been trainedfor tropical warfare but are sent' troops without such a preceding acclimatization to tropical conditions.

' This phenomenon repeats itself later when the sulfamerazine has reached its maximum blood concentration: the few remaining microorganisms which survived the second, namely the penicillin attack by another adaptation, succumb to this unexpected third attack.

It is to'be stressed that this new approach in chemotherapy is distinctly different from the conventional method of combined chemotherapy. This conventionalway aims at continuous effective blood concentrations of two or more different agents. Such continuous efiective concentrations are obtained not by simultaneous administrationbut by. administration of the individual agent at different time intervals, e. g. of penicillin every -2 to 3 hours, sulfadiazine, every 4 to 6 hours, sulfamerazine every 8 to 12 hours.

A further advantage of my new preparation is the prevention of drug-fastness and the synergistic effect of the compound. Though its three mentally produced by exposing a culture of a certain bacillus to low and then steadily increasing concentrations of a bacteriostatic or bacteri- -cidal agent. I have found that a much lesser degree of resistance is acquired if a strain is exposed to, increasing concentrations of two different bacteriostatic agents. No resistance at all develops if several such agents including penicillin are, used. This phenomenon is of major importance for the future of chemotherapy.

As to the synergistic effect of the combination of co-active ingredients: if it is assumed that the chemotherapeutic efficacy of each of the three agents alone is 1, the eflicacy of the combination oftwo is more than 2, and the efiicacy of the combination of all three is more than 3;'

in fact it proves to be far beyond 10 against certain microorganisms. j

Summarized, the resultsand advantages of the new antibacterial therapeutic preparations proposed by me are manifoldl. Microorganisms which would not be killed by any of the three chemotherapeutic agents alone are killed by their combination;

2. Microorganisms which can be killed by each of the three components alone require much smaller amounts of the combined agents for extermination, the required amounts are considerably smaller than would be expected if merely an additive effect would be operative;

3. As a result of the reduction of the total amount of antibacterial agents as set forth under 2, toxic effects of each individual chemotherapeutic agent are avoided;

4. The development of drug fastness, the most essential drawback in chemotherapy is prevented;

5. Due to a true synergistic effect, the treatment with the combination is much more economic;

6. Fewer daily doses are required, and disturbing night doses can be discarded; and

7. Single doses are effective in many infections suchas pneumonia.

.It should be stressed that it was not a priori to be anticipated that several anti-bacterial agents combined would under all circumstances be more effective than each individual agent of such a combination. On the contrary, it has been found that some antibiotics, if combined and administered simultaneously, cancel out their effectiveness and have an anti-bacterial action which is far below theantibacterial action of each individual agent.

- Actually, it has been found that penicillin taken with certain other antibacterial agents such as for instance chloramphenicol, substantially reduces the antibacterial action of penicillin; these agents seem to have mutually antagonistic rather than additive or synergistic eifects.

Contrary thereto, I have obtained. unexpected bacterial effects with a therapeutic preparation above; these ingredients within the indicated ratiorange coact to produce the desired synergistic effects, and presence of an excess of penicil-lin, if any, in said composition will act mainly additively and will not increase the synergistic effects and therefore such excess penicillin is not to be considered an essential coactive ingredien r I have found that particularly good results were obtained with penicillin in the ratio of between 4,000 and 30,000 units of penicillin per each .1 gram of the total amount of sulfadiazine and sulfamerazine.

' Still better results were obtained with penicillin in the proportion of between 10,000 and 20,000 units of penicillin per each .1 gram of sulfadiazine and s'ulfamera'zine.

As sulfonamides, I use preferably sulfadiazine and sulfamerazine in substantially equal amounts; sulfadiazine for its quick absorption, sulfamerazine for its slow absorption .and ex- 'cretion. Sulfadiazine forms a rapid peak of blood concentration and a wave lasting for 4 to 6 hours, sulfamerazine forms a longer wave lasting for 8 to 12 hours.

My present invention will be further illustrated by the following examples. However, I wish to stress that my invention is'not intended to be limited to the same:

Example 1 An antibacterial therapeutic preparation comprising in combination as essential co-active ingredients substantially equal amounts of sulfadiazine and sulfamerazine as sulfonamides and penicillin in the ratio of 10,000 units of penicillin per each .1 gram of sulfonamides.

Example 2 An antibacterial therapeutic preparation comprising in combination as essential co-active ingredients substantially equal amount of sulfadiazine and sulfamerazine as sulfonamides and penicillin in the ratio of about 20,000 units of penicillin per each .1 gram of sulfonamides.

Example 3 An antibacterial therapeutic preparation comprising in combination as essential co-active ingredients substantially equal amounts of sulfadiazine and sulfamerazine as-sulfonamides and penicillin in the ratio of about 5,000 units of penicillin per each .1 gram of sulfonamides.

Example 4 An antibacterial therapeutic preparation in tablet form, each tablet composed of .25 gram of sulfadiazine, .25 gram of sulfamerazine and 50,000 units of penicillin.

Example 5 An antibacterial therapeutic preparation in tablet form, each tablet composed of .25 gram of sulfadiazine, .25 gram of sulfamerazine ,and 100,000 units of penicillin.

Example 6 An antibacterial therapeutic preparationin tablet form, each tablet composed of .50 gram of sulfadiazine, .50 gram of .sulfamerazine and 50,000 units of penicillin.

Example. 7

- diazine and sulfamerazineas sulfonamides and penicillin in the ratio of 30,000 units ofpenicillin per each .1 gram of sulfonamides.

Example-10 .diazine and sulfamerazine as sulfonamides and penicillin in the ratio of 4,000 units of penicillin per each .1 gram of sulfonamides. v

Example 11 Example 12 An antibacterial therapeutic preparation in tablet form, each tablet composed of .20 gram of sulfadiazine, .30 gram of sulfamerazine and 325,000 units of penicillin.

Example 13 An antibacterial therapeutic preparation comprising in combinationas essential co-active ingredients substantially equal amounts of sulfadiazine, sulfamerazine and penicillin in the ratio of 100,000 units of penicillin per each .1 gram of the total amount of sulfadiazine and sulfamerazine.

Example 14 g hand to compare such efiects with the results obtained by separate administration of the single agents of my new preparation.

In one of these tests, thirty-three children with The proportion of penicillin in the combination of co-active ingredients was 8,000 to 10,000.:units per each 0.1 gm. of combined sulfonamides. The medication was given. oneehalf hour; before .or at least two hoursafter meals.

Of thirty-three children, one vomited the tablets and was eliminated from this group. ,ISlX children did not respond to this treatment within forty-eight hours. All of them were revealed by further diagnostic proceduresnot to becases of pneumococcus pneumonia. Two cases; had pulmonary tuberculosis, one primary, atypical pneumonia, one staphylococcus empyema, one

asthmatic bronchitis, and one brochiectasis,

In the: remaining twenty-six cases' the diagnosis of lobar pneumoniaor,bronchopneumonia could be corroborated; Two of these cases were complicated with. bilateral otitis. and one with tonsillitis. ,p

All twenty-six cases responded, to the -single dose of the three combined agentswithin four to twenty-eight hours, or anaverage of .fourteen and eight-tenths hours. The average ,was;only thir teen and three-tenths hours for sixteen children receiving the somewhat higher penicillin doses, as compared with seventeen and two-tenths hours for ten children receiving the lower penicillin proportion.

The temperature of most of these ehildrenwas normal at the 8 a. m. reading following the day the medication was given and remained normal thereafter. i

The results of this test are comparedin the following table with the results of similar tests in which either only sulfadiazine or only penicillin or oral sulfadiazine with intermuscular penicillin were administered. The groups of patients subjected to the variou tests were as far as possible fairly equal as to size, severity of the clinical diagnosis of pneumonia were treated with 40 disease, sex, and racial distribution;

Average Deiervescense Duration within 7 Number of Average Duration Cot Medication Dose Pneufmonia (2i Feve;

ases e are Hours 24 48 48 .x l f g'g s hrs. hrs. hrs.

26 Singleoral dose of pen- 0.1 to 0.2 gm. sulfonamides 3.1 25 1 .0 14.8

icillin plus sulfadiper kg. body weight plus v azine plus suliamer- 8,000 to 10,000'units pen-' azine icillin per 0.1 gm. combined sulfonamides 25 Single oral dose of sul- 0.15 to 0.3 gm. per kg. body 4. 0. 9 4 12 38.4 (average of 19 fadiazine weight cases, excluding 6 cases whichdid not respond to treatment). 23 Full course of oral sul- 0.2 gm. per kg. on first day, 3.7 11 6 6 40.1

iadiazine gillogveiild by 0.1 gm. per 4 a Y 13 Intramuscular penicil- 150,000 to 600,000 units 3.5 9 1 3 21.5

lin daily for 2 to 8 days 20 Full course of oral sul- 0.2 to 0.1 gm. per kg. daily 3. 6 5 11 4 41.8

fadiazine plus intra- 50,000 to 400,000 units muscular penicillin daily ior3 to 12 days a single oral dose of a combination of sulfadiazine, sulfamerazine and penicillin as co-active ingredients in tablet form. Each tablet contained 0.25

gm. sulfadazine, 0.25 gm. sulfamerazine, and

40,000 to 50,000 units of potassium penicillin G. The lower dose of penicillin, 40,000 units per each 0.5 gm. of combined sulfonamides, was applied to ten cases, and the somewhat higher proportion,

50,000 units per 0.5 gm. of sulfonamides, to the rest of the cases.

Children weighing up to 10 kg. received 0.2 gm.

of combined sulfonamides per kg. of body weight;

children between 10 and 20 kg., 0.15 gm.; and children beyond 20 kg., 0.1 gm. of sulfonamides. 76 promptly.

7, Moreover, in the group treated with my new therapeutic preparation, twenty-five of twentysix children became afebrile within twenty-four hours, while in the group treated with one single dose of sulfadiazine, the majority became afebrile only after more'than forty-eight hours.

The above table also includes a comparative group ofpneumonias treated for two to eight days withrepeated intramuscular injections of 150,000 to 600,000 units of penicillin daily. This group indicates that continued treatment with large'parenteral doses of penicillin is not more eifective than single oral doses of the three combined agents. The average duration of fever in the group treated with parenteral penicillin was about twenty-one and five-tenths hours as compared with fourteen and eight-tenths hours in the group treated with single oral doses of the three combined agents in accordance with my 7 present invention.

The last group in the table represents a group of twenty children with lobar pneumonia or bronchopneumonia treated for three to twelve days with a full course of oral sulfadiazine and continued intramuscular injections of penicillin.

The-average duration of fever in this group was "forty-one and eight-tenths hours as compared 'do'sesof .1 gm. of sulfadiazine per kg. of body weight. The average duration of fever in this group was forty and one-tenth hours as compared with fourteen and eight-tenths hours in the group treated with my preparation.

The combination of sulfadiazine, sulfamerazine, and penicillin as co-active ingredients for oral administration is not only suitable for the single dose treatment of pneumonia; it also can be given in repeated doses. A preliminary series of twenty children with tonsillitis, otitis media, lymphadenities, scarlet fever, or pneumonia was treated with three doses a day of the same combination, for one to two days only. Treatment was started in all cases within twelve hours after the onset of the disease. The maximum dosage was 0.1 gm.of combined sulfonamides plus 8,000 t 10,000 units of penicillin per kg. of body weight per day, half of this amount being given as the first dose. Defervescence took place after from eight to thirty-three hours, or an average Fever did not of twenty and two-tenths hours. recur in any of these cases, and the clinical symptoms subsided promptly.

While I have described the invention as embodied in antibacterial preparations, I do not intend to be limited to the details shown, since various modifications and changes maybe made withoutdeparting: in any way from the spirit of my invention.

Without further analysis, the foregoing will sofully reveal thegist of 'my invention'that others can by applying current knowledge readily adapt it for various applications without omit- What I claim as new and desire to secure by Letters Patent is: r

1. An antibacterial therapeutic preparation particularly for peroral administration, comprising as essential co-active ingredients sulfadiazine, sulfamerazine and penicillin in the ratio of between 5,000 and 20,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

2. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients sulfadiazine, sulfamerazine and penicillin in the ratio of between 10,000 and 20,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

3. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients sulfadiazine, sulfamerazine and penicillin in the ratio of about'10,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine'and sulfamerazine.

4. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients substantially equal amounts of sulfadiazine and sulfamerazine; and penicillin in the ratio of between 5,000 and 20,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

5. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients substantially equal amounts of sulfacliazine and sulfamerazine; and penicillin in the ratio of between 10,000 and 20,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

6. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients substantially equal amounts of sulfadiazine and sulfamerazine; and penicillin in the ratio of about 10,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

7. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-aotive ingredients sulfadiazine, sulfamerazine and penicillin in the ratio of between 4,000 and 30,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

8. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients substantially equal amounts of sulfadiazine and sulfamerazine; and penicillin in the ratio of between 4,000 and 30,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

9. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients sulfadiazine, sulfamerazine and penicillin in the ratio of between 4,000 and65,000 units of penicillin per each .1 gram of'the'total amount of said sulfadiazinc and sulfamerazine.

'10. An antibacterial therapeutic preparation particularly for peroral administration comprising as-essential co-active ingredients substantially equal amounts of sulfadiazine and sulfamerazine; .and penicillin in the ratio of between 4,000 and 65,000 units of penicillin per each .1

gram of the total amount of said sulfadiazine and sulfamerazine.

11. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients sulfadiazine, sulfamerazine and penicillin in the ratio of between 4,000 and 100,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

12. An antibacterial therapeutic preparation particularly for peroral administration comprising as essential co-active ingredients substantially equal amounts of sulfadiazine and suliamerazine; and penicillin in the ratio of between 4,000 and 100,000 units of penicillin per each .1 gram of the total amount of said sulfadiazine and sulfamerazine.

HERMANN VOLLMER.

REFERENCES CITED The following references are of record in the file of this patent:

Herrell et al., Penicillin. J. Am. Med. Association, August 12, 1944, volume 125, Number 15, page 1003.

Bigger, Synergic Action of Penicillin and Sulfonamides. J. Am. Med. Association, November 4, 1944, page 666.

Thatcher, Synergistic Action Between the Sulfonamides, Certain Dyes and Streptomycin Against Gram-Negative Bacteria." J. Urology, May 1947, pages 902 to 926.

Lehr, Inhibition of Drug Precipitation in the Urinary Tract by the Use of Sulfonamide Mixtures." Proc. Soc. Exp..Bio1. and Med., January 1945, 14820, pages 11 to 14.

Lehr, Low Toxicity of Sulfonamide Mixtures. II. Combinations of Sulfathiazole, Sulfadiazine and sulfamerazine. Proc. Soc. Exp. Biol. and Med., April 1947, 15806, pages 393 to 399.

New Modern Drugs," April 1946, pages 78, 80, Combisul-DM and Combisul-TD; July 1946, page 139, Aldiazol; October 1947, page 500, Trisulfa and Trisulfin; January 1948, page 564, Tri-Sulfanyl and Trisulficaine. 

11. AN ANTIBACTERIAL THERAPEUTIC PREPARATION PARTICULARLY FOR PERORAL ADMINISTRATION COMPRISING AS ESSENTIAL CO-ACTIVE INGREDIENTS SULFADIAZINE, SULFAMERAZINE AND PENCILLIN IN THE RATIO OF BETWEEN 4,000 AND 100,000 UNITS OF PENICILLIN PER EACH .1 GRAM OF THE TOTAL AMOUNT OF SAID SULFADIAZINE AND SULFAMERAZINE. 